In the recent years, the discovery of a series of mutations in patients with myeloid malignancies has provided insight into the pathogenesis of myelodysplastic syndromes (MDSs), myeloproliferative neoplasms (MPNs), and acute myeloid leukemia (AML). Among these alterations have been mutations in genes, such as IDH1/2, TET2, DNMT3A, and EZH2, which appear to affect DNA and/or histone lysine methylation. Large clinical correlative studies are beginning to decipher the clinical importance, prevalence, and potential prognostic significance of these mutations. Additionally, burgeoning insight into the role of epigenetics in the pathogenesis of myeloid malignancies has prompted increased interest in development of novel therapies which target DNA and histone posttranslational modifications. DNA demethylating agents have been demonstrated to be clinically active in a subset of patients with MDS and AML and are used extensively. However, newer, more specific agents which alter DNA and histone modification are under preclinical study and development and are likely to expand our therapeutic options for these diseases in the near future. Here, we review the current understanding of the clinical importance of these newly discovered mutations in AML and MDS patients. We also discuss exciting developments in DNA methyltransferase inhibitor strategies and the prospect of novel histone lysine methyltransferase inhibitors. 1. Introduction The increasing use of systematic genome-wide discovery efforts in patients with a variety of myeloid malignancies has led to the rapid discovery of a series of recurrent genetic abnormalities underlying these disorders. Remarkably, a large number of these alterations appear to be in genes whose function is known, or suspected, to be involved in epigenetic regulation of gene transcription. In the last 3 years, alone mutations in the genes TET2, IDH1, IDH2, DNMT3a, and EZH2 have all been found in patients with myeloproliferative neoplasms (MPNs), myelodysplastic syndromes (MDSs), and/or acute myeloid leukemia (AML). Although the functional implications of these mutations and how precisely they contribute to abnormal hematopoiesis and leukemogenesis is being heavily investigated and not yet clarified, a number of potentially clinically important implications of these mutations may already be apparent. First, mutations in several of these genes likely hold prognostic importance for patients, and these genetic alterations, thereby, may serve as prognostic markers for risk stratification and aid in therapeutic decision making. Secondly,
References
[1]
F. Ducray, Y. Marie, and M. Sanson, “IDH1 and IDH2 mutations in gliomas,” The The New England Journal of Medicine, vol. 360, p. 2248, 2009.
[2]
C. Hartmann, J. Meyer, J. Balss et al., “Type and frequency of IDH1 and IDH2 mutations are related to astrocytic and oligodendroglial differentiation and age: a study of 1,010 diffuse gliomas,” Acta Neuropathologica, vol. 118, no. 4, pp. 469–474, 2009.
[3]
D. W. Parsons, S. Jones, X. Zhang et al., “An integrated genomic analysis of human glioblastoma multiforme,” Science, vol. 321, no. 5897, pp. 1807–1812, 2008.
[4]
M. Sanson, Y. Marie, S. Paris et al., “Isocitrate dehydrogenase 1 codon 132 mutation is an important prognostic biomarker in gliomas,” Journal of Clinical Oncology, vol. 27, no. 25, pp. 4150–4154, 2009.
[5]
T. Watanabe, S. Nobusawa, P. Kleihues, and H. Ohgaki, “IDH1 mutations are early events in the development of astrocytomas and oligodendrogliomas,” American Journal of Pathology, vol. 174, no. 4, pp. 1149–1153, 2009.
[6]
Y. Sonoda, T. Kumabe, T. Nakamura et al., “Analysis of IDH1 and IDH2 mutations in Japanese glioma patients,” Cancer Science, vol. 100, no. 10, pp. 1996–1998, 2009.
[7]
E. R. Mardis, L. Ding, D. J. Dooling et al., “Recurring mutations found by sequencing an acute myeloid leukemia genome,” The New England Journal of Medicine, vol. 361, no. 11, pp. 1058–1066, 2009.
[8]
A. Tefferi, T. L. Lasho, O. Abdel-Wahab et al., “IDH1 and IDH2 mutation studies in 1473 patients with chronic-, fibrotic- or blast-phase essential thrombocythemia, polycythemia vera or myelofibrosis,” Leukemia, vol. 24, no. 7, pp. 1302–1309, 2010.
[9]
S. Gross, R. A. Cairns, M. D. Minden et al., “Cancer-associated metabolite 2-hydroxyglutarate accumulates in acute myelogenous leukemia with isocitrate dehydrogenase 1 and 2 mutations,” Journal of Experimental Medicine, vol. 207, no. 2, pp. 339–344, 2010.
[10]
S. Abbas, S. Lugthart, F. G. Kavelaars et al., “Acquired mutations in the genes encoding IDH1 and IDH2 both are recurrent aberrations in acute myeloid leukemia: prevalence and prognostic value,” Blood, vol. 116, no. 12, pp. 2122–2126, 2010.
[11]
N. Boissel, O. Nibourel, A. Renneville et al., “Prognostic impact of isocitrate dehydrogenase enzyme isoforms 1 and 2 mutations in acute myeloid leukemia: a study by the acute leukemia French association group,” Journal of Clinical Oncology, vol. 28, no. 23, pp. 3717–3723, 2010.
[12]
G. Marcucci, K. Maharry, Y. Z. Wu et al., “IDH1 and IDH2 gene mutations identify novel molecular subsets within de novo cytogenetically normal acute myeloid leukemia: a cancer and leukemia group B study,” Journal of Clinical Oncology, vol. 28, no. 14, pp. 2348–2355, 2010.
[13]
P. Paschka, R. F. Schlenk, V. I. Gaidzik et al., “IDH1 and IDH2 mutations are frequent genetic alterations in acute myeloid leukemia and confer adverse prognosis in cytogenetically normal acute myeloid leukemia with NPM1 mutation without FLT3 internal tandem duplication,” Journal of Clinical Oncology, vol. 28, no. 22, pp. 3636–3643, 2010.
[14]
S. Schnittger, C. Haferlach, M. Ulke, T. Alpermann, W. Kern, and T. Haferlach, “IDH1 mutations are detected in 6.6% of 1414 AML patients and are associated with intermediate risk karyotype and unfavorable prognosis in adults younger than 60 years and unmutated NPM1 status,” Blood, vol. 116, no. 25, pp. 5486–5496, 2010.
[15]
P. S. Ward, J. Patel, D. R. Wise et al., “The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzyme activity converting α-ketoglutarate to 2-hydroxyglutarate,” Cancer Cell, vol. 17, no. 3, pp. 225–234, 2010.
[16]
H. Yan, D. W. Parsons, G. Jin et al., “IDH1 and IDH2 mutations in gliomas,” The New England Journal of Medicine, vol. 360, no. 8, pp. 765–773, 2009.
[17]
L. Dang, D. W. White, S. Gross et al., “Cancer-associated IDH1 mutations produce 2-hydroxyglutarate,” Nature, vol. 462, no. 7274, pp. 739–744, 2009.
[18]
Z. J. Reitman, D. W. Parsons, and H. Yan, “IDH1 and IDH2: not your typical oncogenes,” Cancer Cell, vol. 17, no. 3, pp. 215–216, 2010.
[19]
Z. J. Reitman and H. Yan, “Isocitrate dehydrogenase 1 and 2 mutations in cancer: alterations at a crossroads of cellular metabolism,” Journal of the National Cancer Institute, vol. 102, no. 13, pp. 932–941, 2010.
[20]
S. K？lker, V. Pawlak, B. Ahlemeyer et al., “NMDA receptor activation and respiratory chain complex V inhibition contribute to neurodegeneration in D-2-hydroxyglutaric aciduria,” European Journal of Neuroscience, vol. 16, no. 1, pp. 21–28, 2002.
[21]
A. Latini, K. Scussiato, R. B. Rosa et al., “D-2-hydroxyglutaric acid induces oxidative stress in cerebral cortex of young rats,” European Journal of Neuroscience, vol. 17, no. 10, pp. 2017–2022, 2003.
[22]
C. Frezza, D. A. Tennant, and E. Gottlieb, “IDH1 mutations in gliomas: when an enzyme loses its grip,” Cancer Cell, vol. 17, no. 1, pp. 7–9, 2010.
[23]
M. E. Figueroa, O. Abdel-Wahab, C. Lu et al., “Leukemic IDH1 and IDH2 mutations result in a hypermethylation phenotype, disrupt TET2 function, and impair hematopoietic differentiation,” Cancer Cell, vol. 18, no. 6, pp. 553–567, 2010.
[24]
J. Boultwood and J. S. Wainscoat, “Gene silencing by DNA methylation in haematological malignancies,” British Journal of Haematology, vol. 138, no. 1, pp. 3–11, 2007.
[25]
G. Leone, L. Teofili, M. T. Voso, and M. Lübbert, “DNA methylation and demethylating drugs in myelodysplastic syndromes and secondary leukemias,” Haematologica, vol. 87, no. 12, pp. 1324–1341, 2002.
[26]
M. E. Figueroa, S. Lugthart, Y. Li et al., “DNA methylation signatures identify biologically distinct subtypes in acute myeloid leukemia,” Cancer Cell, vol. 17, no. 1, pp. 13–27, 2010.
[27]
S. D. Gore, S. Baylin, E. Sugar et al., “Combined DNA methyltransferase and histone deacetylase inhibition in the treatment of myeloid neoplasms,” Cancer Research, vol. 66, no. 12, pp. 6361–6369, 2006.
[28]
R. Khan, J. Schmidt-Mende, M. Karimi et al., “Hypomethylation and apoptosis in 5-azacytidine-treated myeloid cells,” Experimental Hematology, vol. 36, no. 2, pp. 149–157, 2008.
[29]
S. Lugthart, M. E. Figueroa, E. Bindels et al., “Aberrant DNA hypermethylation signature in acute myeloid leukemia directed by EVI1,” Blood, vol. 117, no. 1, pp. 234–241, 2011.
[30]
S. Ito, A. C. D'Alessio, O. V. Taranova, K. Hong, L. C. Sowers, and Y. Zhang, “Role of Tet proteins in 5mC to 5hmC conversion, ES-cell self-renewal and inner cell mass specification,” Nature, vol. 466, no. 7310, pp. 1129–1133, 2010.
[31]
M. Tahiliani, K. P. Koh, Y. Shen et al., “Conversion of 5-methylcytosine to 5-hydroxymethylcytosine in mammalian DNA by MLL partner TET1,” Science, vol. 324, no. 5929, pp. 930–935, 2009.
[32]
W. Xu, H. Yang, Y. Liu et al., “Oncometabolite 2-hydroxyglutarate is a competitive inhibitor of α-ketoglutarate-dependent dioxygenases,” Cancer Cell, vol. 19, no. 1, pp. 17–30, 2011.
[33]
Y. Wang, J. Wysocka, J. Sayegh et al., “Human PAD4 regulates histone arginine methylation levels via demethylimination,” Science, vol. 306, no. 5694, pp. 279–283, 2004.
[34]
Y. Shi, F. Lan, C. Matson et al., “Histone demethylation mediated by the nuclear amine oxidase homolog LSD1,” Cell, vol. 119, no. 7, pp. 941–953, 2004.
[35]
R. J. Klose, K. Yamane, Y. Bae et al., “The transcriptional repressor JHDM3A demethylates trimethyl histone H3 lysine 9 and lysine 36,” Nature, vol. 442, no. 7100, pp. 312–316, 2006.
[36]
K. Yamane, C. Toumazou, Y. I. Tsukada et al., “JHDM2A, a JmjC-containing H3K9 demethylase, facilitates transcription activation by androgen receptor,” Cell, vol. 125, no. 3, pp. 483–495, 2006.
[37]
D. J. Seward, G. Cubberley, S. Kim et al., “Demethylation of trimethylated histone H3 Lys4 in vivo by JARID1 JmjC proteins,” Nature Structural and Molecular Biology, vol. 14, no. 3, pp. 240–242, 2007.
[38]
K. Agger, P. A. C. Cloos, J. Christensen et al., “UTX and JMJD3 are histone H3K27 demethylases involved in HOX gene regulation and development,” Nature, vol. 449, no. 7163, pp. 731–734, 2007.
[39]
B. Chang, Y. Chen, Y. Zhao, and R. K. Bruick, “JMJD6 is a histone arginine demethylase,” Science, vol. 318, no. 5849, pp. 444–447, 2007.
[40]
R. F. Schlenk, K. D？hner, J. Krauter et al., “Mutations and treatment outcome in cytogenetically normal acute myeloid leukemia,” The New England Journal of Medicine, vol. 358, no. 18, pp. 1909–1918, 2008.
[41]
S. Fr？hling, R. F. Schlenk, J. Breitruck et al., “Prognostic significance of activating FLT3 mutations in younger adults (16 to 60 years) with acute myeloid leukemia and normal cytogenetics: a study of the AML study group Ulm,” Blood, vol. 100, no. 13, pp. 4372–4380, 2002.
[42]
S. Schnittger, C. Schoch, W. Kern et al., “Nucleophosmin gene mutations are predictors of favorable prognosis in acute myelogenous leukemia with a normal karyotype,” Blood, vol. 106, no. 12, pp. 3733–3739, 2005.
[43]
K. D？hner, R. F. Schlenk, M. Habdank et al., “Mutant nucleophosmin (NPM1) predicts favorable prognosis in younger adults with acute myeloid leukemia and normal cytogenetics: interaction with other gene mutations,” Blood, vol. 106, no. 12, pp. 3740–3746, 2005.
[44]
S. Fr？hling, R. F. Schlenk, I. Stolze et al., “CEBPA mutations in younger adults with acute myeloid leukemia and normal cytogenetics: prognostic relevance and analysis of cooperating mutations,” Journal of Clinical Oncology, vol. 22, no. 4, pp. 624–633, 2004.
[45]
C. Preudhomme, C. Sagot, N. Boissel et al., “Favorable prognostic significance of CEBPA mutations in patients with de novo acute myeloid leukemia: a study from the Acute Leukemia French Association (ALFA),” Blood, vol. 100, no. 8, pp. 2717–2723, 2002.
[46]
C. L. Green, C. M. Evans, R. K. Hills, A. K. Burnett, D. C. Linch, and R. E. Gale, “The prognostic significance of IDH1 mutations in younger adult patients with acute myeloid leukemia is dependent on FLT3/ITD status,” Blood, vol. 116, no. 15, pp. 2779–2782, 2010.
[47]
S. Schnittger, C. Haferlach, T. Alpermann, W. Kern, and T. Haferlach, “IDH mutations can be detected In 28.7% of all normal karyotype AML and have unfavourable impact on the NPM1+/FLT3-ITD- genotype,” Blood, vol. 116, 2010, ASH Annual Meeting Abstracts, Abstract 102.
[48]
F. Ravandi, K. P. Patel, R. Luthra, et al., “Prognostic significance of mutations in isocitrate dehydrogenase (IDH) enzyme isoforms 1 and 2 and single nucleotide polymorphisms (SNP) in IDH1, in patients with acute myeloid leukemia treated with high dose cytarabine and idarubicin induction,” Blood, vol. 116, 2010, ASH Annual Meeting Abstracts, Abstract 2706.
[49]
D. Caramazza, T. Lasho, C. Finke, et al., “IDH mutations and trisomy 8 in myelodysplastic syndromes and acute myeloid leukemia,” Blood, vol. 116, 2010, ASH Annual Meeting Abstracts, Abstract 4009.
[50]
F. Delhommeau, S. Dupont, V. D. Valle et al., “Mutation in TET2 in myeloid cancers,” The New England Journal of Medicine, vol. 360, no. 22, pp. 2289–2301, 2009.
[51]
O. Abdel-Wahab, A. Mullally, C. Hedvat et al., “Genetic characterization of TET1, TET2, and TET3 alterations in myeloid malignancies,” Blood, vol. 114, no. 1, pp. 144–147, 2009.
[52]
A. M. Jankowska, H. Szpurka, R. V. Tiu et al., “Loss of heterozygosity 4q24 and TET2 mutations associated with myelodysplastic/myeloproliferative neoplasms,” Blood, vol. 113, no. 25, pp. 6403–6410, 2009.
[53]
A. Tefferi, A. Pardanani, K. H. Lim et al., “TET2 mutations and their clinical correlates in polycythemia vera, essential thrombocythemia and myelofibrosis,” Leukemia, vol. 23, no. 5, pp. 905–911, 2009.
[54]
S. M. C. Langemeijer, R. P. Kuiper, M. Berends et al., “Acquired mutations in TET2 are common in myelodysplastic syndromes,” Nature Genetics, vol. 41, no. 7, pp. 838–842, 2009.
[55]
O. Abdel-Wahab, T. Manshouri, J. Patel et al., “Genetic analysis of transforming events that convert chronic myeloproliferative neoplasms to leukemias,” Cancer Research, vol. 70, no. 2, pp. 447–452, 2010.
[56]
J. U. Guo, Y. Su, C. Zhong, G. L. Ming, and H. Song, “Hydroxylation of 5-methylcytosine by TET1 promotes active DNA demethylation in the adult brain,” Cell, vol. 145, no. 3, pp. 423–434, 2011.
[57]
M. Ko, Y. Huang, A. M. Jankowska et al., “Impaired hydroxylation of 5-methylcytosine in myeloid cancers with mutant TET2,” Nature, vol. 468, no. 7325, pp. 839–843, 2010.
[58]
O. Kosmider, V. Gelsi-Boyer, M. Ciudad et al., “TET2 gene mutation is a frequent and adverse event in chronic myelomonocytic leukemia,” Haematologica, vol. 94, no. 12, pp. 1676–1681, 2009.
[59]
O. Nibourel, O. Kosminder, M. Cheok, et al., “Association of TET2 alterations with NPM1 mutations and prognostic value in de novo Acute Myeloid Leukemia (AML),” Blood, vol. 114, no. 22, 2009.
[60]
V. Gaidzik, R. F. Schlenk, P. Paschka, et al., “TET2 mutations in Acute Myeloid Leukemia (AML): results on 783 patients treated within the AML HD98A study of the AML Study Group (AMLSG),” Blood, vol. 116, 2010.
[61]
O. Kosmider, V. Gelsi-Boyer, M. Cheok et al., “TET2 mutation is an independent favorable prognostic factor in myelodysplastic syndromes (MDSs),” Blood, vol. 114, no. 15, pp. 3285–3291, 2009.
[62]
K. H. Metzeler, K. Maharry, M. D. Radmacher et al., “TET2 mutations improve the new European LeukemiaNet risk classification of acute myeloid leukemia: a cancer and leukemia group B study,” Journal of Clinical Oncology, vol. 29, no. 10, pp. 1373–1381, 2011.
[63]
T. J. Ley, L. Ding, M. J. Walter et al., “DNMT3A mutations in acute myeloid leukemia,” The New England Journal of Medicine, vol. 363, no. 25, pp. 2424–2433, 2010.
[64]
Y. Yamashita, J. Yuan, I. Suetake et al., “Array-based genomic resequencing of human leukemia,” Oncogene, vol. 29, no. 25, pp. 3723–3731, 2010.
[65]
X. J. Yan, J. Xu, Z. H. Gu et al., “Exome sequencing identifies somatic mutations of DNA methyltransferase gene DNMT3A in acute monocytic leukemia,” Nature Genetics, vol. 43, no. 4, pp. 309–315, 2011.
[66]
M. J. Walter, L. Ding, D. Shen, et al., “Recurrent DNMT3A mutations in patients with myelodysplastic syndromes,” Leukemia. In press.
[67]
O. Abdel-Wahab, A. Pardanani, R. Rampal, T. L. Lasho, R. L. Levine, and A. Tefferi, “DNMT3A mutational analysis in primary myelofibrosis, chronic myelomonocytic leukemia and advanced phases of myeloproliferative neoplasms,” Leukemia. In press.
[68]
R. D. Morin, N. A. Johnson, T. M. Severson et al., “Somatic mutations altering EZH2 (Tyr641) in follicular and diffuse large B-cell lymphomas of germinal-center origin,” Nature Genetics, vol. 42, no. 2, pp. 181–185, 2010.
[69]
O. Abdel-Wahab, A. Pardanani, J. Patel, et al., “Concomitant analysis of EZH2 and ASXL1 mutations in myelofibrosis, chronic myelomonocytic leukemia and blast-phase myeloproliferative neoplasms,” Leukemia. In press.
[70]
T. Ernst, A. J. Chase, J. Score et al., “Inactivating mutations of the histone methyltransferase gene EZH2 in myeloid disorders,” Nature Genetics, vol. 42, no. 8, pp. 722–726, 2010.
[71]
G. Nikoloski, S. M. C. Langemeijer, R. P. Kuiper et al., “Somatic mutations of the histone methyltransferase gene EZH2 in myelodysplastic syndromes,” Nature Genetics, vol. 42, no. 8, pp. 665–667, 2010.
[72]
E. Viré, C. Brenner, R. Deplus et al., “The Polycomb group protein EZH2 directly controls DNA methylation,” Nature, vol. 439, no. 7078, pp. 871–874, 2006.
[73]
K. D？hner, J. Brown, U. Hehmann et al., “Molecular cytogenetic characterization of a critical region in bands 7q35-q36 commonly deleted in malignant myeloid disorders,” Blood, vol. 92, no. 11, pp. 4031–4035, 1998.
[74]
M. M. Le Beau, R. Espinosa III, E. M. Davis, J. D. Eisenbart, R. A. Larson, and E. D. Green, “Cytogenetic and molecular delineation of a region of chromosome 7 commonly deleted in malignant myeloid diseases,” Blood, vol. 88, no. 6, pp. 1930–1935, 1996.
[75]
G. Garcia-Manero, S. D. Gore, C. R. Cogle, et al., “Evaluation of oral azacitidine using extended treatment schedules: a phase I study,” Blood, vol. 116, 2010.
[76]
A. S. Yang, K. D. Doshi, S. W. Choi et al., “DNA methylation changes after 5-aza-2′-deoxycytidine therapy in patients with leukemia,” Cancer Research, vol. 66, no. 10, pp. 5495–5503, 2006.
[77]
L. Zhou, X. Cheng, B. A. Connolly, M. J. Dickman, P. J. Hurd, and D. P. Hornby, “Zebularine: a novel DNA methylation inhibitor that forms a covalent complex with DNA methyltransferases,” Journal of Molecular Biology, vol. 321, no. 4, pp. 591–599, 2002.
[78]
J. C. Cheng, C. B. Matsen, F. A. Gonzales et al., “Inhibition of DNA methylation and reactivation of silenced genes by zebularine,” Journal of the National Cancer Institute, vol. 95, no. 5, pp. 399–409, 2003.
[79]
J. C. Cheng, C. B. Yoo, D. J. Weisenberger et al., “Preferential response of cancer cells to zebularine,” Cancer Cell, vol. 6, no. 2, pp. 151–158, 2004.
[80]
A. J. Davis, K. A. Gelmon, L. L. Siu et al., “Phase I and pharmacologic study of the human DNA methyltransferase antisense oligodeoxynucleotide MG98 given as a 21-day continuous infusion every 4 weeks,” Investigational New Drugs, vol. 21, no. 1, pp. 85–97, 2003.
[81]
D. J. Stewart, R. C. Donehower, E. A. Eisenhauer et al., “A phase I pharmacokinetic and pharmacodynamic study of the DNA methyltransferase 1 inhibitor MG98 administered twice weekly,” Annals of Oncology, vol. 14, no. 5, pp. 766–774, 2003.
[82]
R. B. Klisovic, W. Stock, S. Cataland et al., “A phase I biological study of MG98, an oligodeoxynucleotide antisense to DNA methyltransferase 1, in patients with high-risk myelodysplasia and acute myeloid leukemia,” Clinical Cancer Research, vol. 14, no. 8, pp. 2444–2449, 2008.
[83]
E. Winquist, J. Knox, J. P. Ayoub et al., “Phase II trial of DNA methyltransferase 1 inhibition with the antisense oligonucleotide MG98 in patients with metastatic renal carcinoma: a National Cancer Institute of Canada Clinical Trials Group investigational new drug study,” Investigational New Drugs, vol. 24, no. 2, pp. 159–167, 2006.
[84]
B. Brueckner, R. G. Boy, P. Siedlecki et al., “Epigenetic reactivation of tumor suppressor genes by a novel small-molecule inhibitor of human DNA methyltransferases,” Cancer Research, vol. 65, no. 14, pp. 6305–6311, 2005.
[85]
D. Kuck, N. Singh, F. Lyko, and J. L. Medina-Franco, “Novel and selective DNA methyltransferase inhibitors: docking-based virtual screening and experimental evaluation,” Bioorganic and Medicinal Chemistry, vol. 18, no. 2, pp. 822–829, 2010.
[86]
R. Itzykson, O. Kosmider, T. Cluzeau, et al., “Impact of TET2 mutations on response rate to azacitidine in myelodysplastic syndromes and low blast count acute myeloid leukemias,” Leukemia. In press.
[87]
D. A. Pollyea, A. Raval, B. Kusler, J. R. Gotlib, A. A. Alizadeh, and B. S. Mitchell, “Impact of TET2 mutations on mRNA expression and clinical outcomes in MDS patients treated with DNA methyltransferase inhibitors,” Journal of Hematology & Oncology, 2010.
[88]
A. V. Krivtsov and S. A. Armstrong, “MLL translocations, histone modifications and leukaemia stem-cell development,” Nature Reviews Cancer, vol. 7, no. 11, pp. 823–833, 2007.
[89]
G. G. Wang, L. Cai, M. P. Pasillas, and M. P. Kamps, “NUP98-NSD1 links H3K36 methylation to Hox-A gene activation and leukaemogenesis,” Nature Cell Biology, vol. 9, no. 7, pp. 804–812, 2007.
[90]
C. Meyer, E. Kowarz, J. Hofmann et al., “New insights to the MLL recombinome of acute leukemias,” Leukemia, vol. 23, no. 8, pp. 1490–1499, 2009.
[91]
S. Y. Jo, E. M. Granowicz, I. Maillard, D. Thomas, and J. L. Hess, “Requirement for Dot1l in murine postnatal hematopoiesis and leukemogenesis by MLL translocation,” Blood, vol. 117, no. 18, pp. 4759–4768, 2011.
[92]
K. Bernt, N. Zhu, J. Faber, et al., “Demonstration of a role for Dot1l in MLL-rearranged leukemia using a conditional loss of function model,” Blood, vol. 116, 2010.
[93]
R. Pollock, S. R. Daigle, E. J. Olhava, et al., “Selective killing of mixed lineage leukemia cells by a potent small-molecule DOT1L inhibitor,” Blood, vol. 116, 2010.
[94]
A. V. Krivtsov, Z. Feng, M. E. Lemieux et al., “H3K79 methylation profiles define murine and human MLL-AF4 leukemias,” Cancer Cell, vol. 14, no. 5, pp. 355–368, 2008.
[95]
A. Bursen, K. Schwabe, B. Rüster et al., “The AF4·MLL fusion protein is capable of inducing ALL in mice without requirement of MLL·AF4,” Blood, vol. 115, no. 17, pp. 3570–3579, 2010.
[96]
A. Benedikt, S. Baltruschat, B. Scholz et al., “The leukemogenic AF4-MLL fusion protein causes P-TEFb kinase activation and altered epigenetic signatures,” Leukemia, vol. 25, pp. 135–144, 2010.
[97]
A. T. Nguyen, B. Xiao, R. L. Neppl et al., “DOT1L regulates dystrophin expression and is critical for cardiac function,” Genes and Development, vol. 25, no. 3, pp. 263–274, 2011.
[98]
A. Jankowska, H. Makishima, R. V. Tiu, et al., “Mutational spectrum in chronic myelomonocytic leukemia includes genes associated with epigenetic regulation such as UTX and EZH2,” Blood, vol. 116, 2010.
[99]
M. Allan, S. Manku, E. Therrien et al., “N-benzyl-1-heteroaryl-3-(trifluoromethyl)-1H-pyrazole-5-carboxamides as inhibitors of co-activator associated arginine methyltransferase 1 (CARM1),” Bioorganic and Medicinal Chemistry Letters, vol. 19, no. 4, pp. 1218–1223, 2009.
[100]
J. Eeckhoute, E. K. Keeton, M. Lupien, S. A. Krum, J. S. Carroll, and M. Brown, “Positive cross-regulatory loop ties GATA-3 to estrogen receptor α expression in breast cancer,” Cancer Research, vol. 67, no. 13, pp. 6477–6483, 2007.
[101]
Y. R. Kim, B. K. Lee, R. Y. Park et al., “Differential CARM1 expression in prostate and colorectal cancers,” BioMed Central Cancer, vol. 10, p. 197, 2010.
